Schistosomiasis is a serious global health problem caused by intravascular parasitic worms called schistosomes. Currently ~200 million people are infected with these parasites. Tens of millions of people have chronic morbidity and new treatments are needed. We have identified a carbonic anhydrase enzyme (SmCA) that is an accessible and rational target of such treatment. The enzyme is expressed on the surface of intravascular stage schistosomes. Parasites with diminished SmCA (achieved through RNAi) fail to establish a robust infection in mice. Chemical compounds that mimic the RNAi effect and inhibit SmCA should likewise debilitate the worms. Carbonic anhydrases (CAs) are extremely druggable proteins and several drugs that target vertebrate CA isoforms are currently used to treat a number of conditions in humans. The aim of this application is to identify potent and specific SmCA inhibitors to test the hypothesis that these can form the basis for a novel anti-schistosome therapy. We partner here with Dr. Claudiu Supuran, a world leader in carbonic anhydrases and their inhibitors. Dr. Supuran has amassed a defined, unique set of ~400 CA inhibitors and chemical variants for testing here with SmCA. To facilitate testing, we have expressed SmCA as a secreted recombinant protein in a mammalian expression system and we have purified the active enzyme from the medium. Potent SmCA inhibitors identified by Dr. Supuran will be subject to a validated secondary screen in which their ability to decrease CA activity in living parasites in vitro is measured. Here, we will test all 3 major species of human schistosome to identify pan-schistosome CA inhibitors. We believe that our approach will yield effective schistosome CA inhibitors that will debilitate the parasites and form the basis of a new and urgently needed therapy to treat schistosomiasis, a neglected, global condition that remains a source of tremendous death and morbidity in the 21st century.